Crytalline form of (s)-2 ethoxy -3-[4-(2-{4- methanesulfonyloxyphenyl} ethoxy)phenyl]propanoic acid

ABSTRACT

The present invention relates to a novel crystalline form of the compound (S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid, shown by formula (I), or a pharmaceutically-acceptable salt thereof, and solvates thereof. The invention also concerns methods of treating one or more metabolic disease conditions, particularly those associated with Insulin Resistance Syndrome, and the use of a crystalline form of the compound, or a pharmaceutically-acceptable salt thereof, or a solvate thereof, in the manufacture of a medicament for use in one or more of said conditions. The invention further concerns pharmaceutical compositions containing a crystalline form of the compound, or a pharmaceutically-acceptable salt thereof, or a solvate thereof, as active ingredient, as well as processes for the manufacture of a crystalline form of the compound, or a pharmaceutically-acceptable salt thereof, or a solvate thereof.

The present invention relates to a crystalline form of the compound(S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid as shown in formula I below

or a pharmaceutically-acceptable salt thereof, and solvates thereof. Theinvention also concerns methods of treating one or more metabolicdisease conditions, particularly those associated with InsulinResistance Syndrome, and the use of a crystalline form of the compound,or a pharmaceutically-acceptable salt thereof, or a solvate thereof, inthe manufacture of a medicament for therapeutic use in one or more ofsaid metabolic diseases.

The invention further concerns pharmaceutical compositions containing acrystalline form of the compound, or a pharmaceutically-acceptable saltthereof, or a solvate thereof, as active ingredient, as well asprocesses for the manufacture of a crystalline form of the compound, ora pharmaceutically-acceptable salt thereof, or a solvate thereof.

In the formulation of drug compositions, it is important for the drugsubstance to be in a form in which it can be conveniently handled andprocessed. This is of importance, not only from the point of view ofobtaining a commercially viable manufacturing process, but also from thepoint of subsequent manufacture of pharmaceutical formulationscomprising the active compound.

Chemical stability, solid state stability, and shelf life of the activeingredients are also very important factors. The drug substance, andcompositions containing it, should be capable of being effectivelystored over appreciable periods of time, without exhibiting asignificant change in the active component's physico-chemicalcharacteristics (e.g. its chemical composition, density, hygroscopicityand solubility).

Moreover, it is also important to be able to provide drug in a formwhich is as chemically-pure as possible.

Amorphous materials may present significant problems in this regard. Forexample, such materials are typically more difficult to handle and toformulate than crystalline material, provide for unreliable solubility,and are often found to be unstable and chemically impure.

The skilled person will appreciate that, if a drug can be readilyobtained in a stable crystalline form, the above problems may be solved.

Thus, in the manufacture of commercially viable, and pharmaceuticallyacceptable, drug compositions, it is desirable, wherever possible, toprovide drug in a substantially crystalline, and stable, form.

It is to be noted, however, that this goal is not always achievable.Indeed, typically, it is not possible to predict, from molecularstructure alone, what the crystallisation behaviour of a compound willbe, and this can usually only be determined empirically.

The above compound is intended for therapeutic use in Insulin ResistanceSyndrome (IRS), which refers to a cluster of manifestations includinginsulin resistance with accompanying hyperinsulinaemia, possible type 2diabetes mellitus, arterial hypertension, central (visceral) obesity,dyslipidaemia observed as deranged lipoprotein levels typicallycharacterised by elevated VLDL (very low density lipoproteins) andreduced HDL (high density lipoproteins) concentrations and reducedfibrinolysis.

Recent epidemiological research has documented that individuals withinsulin resistance run a greatly increased risk of cardiovascularmorbidity and mortality, notably suffering from myocardial infarctionand stroke. In type 2 diabetes mellitus atherosclerosis relatedconditions cause up to 80% of all deaths.

In clinical medicine there is awareness of the need to increase theinsulin sensitivity in IRS suffering patients and thus to correct thedyslipidaemia which is considered to cause the accelerated progress ofatherosclerosis. However, currently this is not a universally welldefined disease.

The present invention relates to a crystalline solid form of thecompound of formula I. Significant advantages can arise when thecompound of formula I can be isolated in a crystalline form, forexample, in the manufacture of the compound to the purity levels anduniformity required for regulatory approval and for ease and uniformityof formulation.

We have isolated the compound of formula I as a crystalline solid. Theparticular crystalline form isolated exists in a form which issubstantially or essentially free of solvent (hereinafter referred to as“the anhydrous form”). Alternatively a solvated form may be produced,for example, a hydrated form.

We present as a feature of the invention a crystalline form of acompound of formula I, or a solvate thereof. In an alternative featureof the invention we present a crystalline form of apharmaceutically-acceptable salt of the compound of formula I, or asolvate thereof.

By the use of the term “solvated” we also include hydrated. By the useof the term “a crystalline form” we mean each and everyone possiblecrystalline form of the compound of formula I, preferably an anhydrousform.

A crystalline form of the compound of formula I can be defined byreference to its melting point, powder X-ray diffraction pattern andsingle-crystal X-ray data.

The melting point of the crystalline form of the compound of formula Igenerally depends on the level of purity and may be determined byconventional procedures well known in the art, for example, bydifferential scanning calorimetry (DSC). Typically, the anhydrous formhas a melting point which is in the range 82-92° C., for example about85-89° C.

The anhydrous form has an X-ray powder diffraction pattern containingspecific peaks of high intensity at 6.2, 4.47 and 4.15 Å. Additionalspecific peaks of lower relative intensity to the first peaks are at4.69, 3.64, 3.60 and 3.45 Å.

A crystalline form of a compound of formula I may be obtained from anon-crystalline form of a compound of formula I, by crystallisation froma suitable solvent (including organic solvents, aqueous solutions andmixtures thereof), such as toluene and ethyl acetate, or a mixture ofsolvents, such as a mixture of ethanol/water, isopropanol/water ortoluene/isooctane. To initiate crystallisation seeding with crystallinecompound of formula I may be required. Crystallisation of the compoundfrom an appropriate solvent system may be achieved by attainingsupersaturation, for example, by cooling, by solvent evaporation and/orby the addition of an anti-solvent (a solvent in which the compound offormula I is poorly soluble, examples of suitable anti-solvents includeheptane or isooctane). Crystallisation temperatures and times will varydepending upon the concentration of the compound of formula I insolution, the solvent system used and the method of crystallisationadopted.

A crystalline form of the compound of formula I may be isolated usingtechniques well known to those skilled in the art, for example, bydecanting, filtration or centrifuging. Similarly the crystalline formmay be dried in accordance with well known procedures.

Optional recrystallisation step(s) may be performed using the same ordifferent solvent systems to reduce further impurities, such asamorphous material, chemical impurities, or to convert the crystallineform into a solvated/hydrated form or an anhydrous form.

Preferably crystallisation is carried out directly from the reactionsolution. Alternatively crystallisation is performed from a subsequentsolution.

A further feature of the invention is a process for the production of acrystalline form of a compound of formula I which comprisescrystallising the compound of formula I.

By the use of the term “the anhydrous form”, we do not exclude thepresence of some solvent, including water, within the crystal latticestructure. Solvent, including water, may also be present outside thecrystal lattice structure.

A feature of the invention is a crystalline form of a compound offormula I, as described above, for use in medical therapy.

According to a further feature of the invention there is provided apharmaceutical composition which comprises a crystalline form of acompound of formula I, as described above, in association with apharmaceutically-acceptable diluent or carrier. The use of a crystallineform of a compound of formula I, as described above, in the preparationof a pharmaceutical composition by bringing into association acrystalline form of a compound of formula I with apharmaceutically-acceptable diluent or carrier.

The composition may be in a form suitable for oral use, for example atablet, capsule, aqueous or oily solution, suspension or emulsion; fortopical use, for example a cream, ointment, gel or aqueous or oilysolution or suspension; for nasal use, for example a snuff, nasal sprayor nasal drops; for vaginal or rectal use, for example a suppository;for administration by inhalation, for example as a finely divided powdersuch as a dry powder, a microcrystalline form or a liquid aerosol; forsub-lingual or buccal use, for example a tablet or capsule; or forparenteral use (including intravenous, subcutaneous, intramuscular,intravascular or infusion), for example a sterile aqueous or oilysolution or suspension.

In general the above compositions may be prepared in a conventionalmanner using conventional excipients.

The amount of the crystalline form of a compound of formula I, asdescribed above, that is combined with one or more excipients to producea single dosage form will necessarily vary depending upon the hosttreated and the particular route of administration.

For example, a formulation intended for oral administration to humanswill generally contain, for example, from 0.001 mg to 50 mg of activeagent mixed with an appropriate and convenient amount of excipient(s)which may vary from about 10 to about 99.9999 percent by weight of thetotal composition.

The invention also includes the use of the crystalline compound of theinvention, as described above in the production of a medicament for usein:

(i) treating dyslipidaemia;

(ii) treating type 2 diabetes mellitus;

(iii) treating hyperglycaemia;

(iv) treating hyperinsulinaemia;

(v) treating hyperlipidaemia;

(vi) treating arterial hypertension; and/or

(vii) treating abdominal obesity.

The invention also includes a method of producing an effect as definedhereinbefore or treating a disease or disorder as defined hereinbeforewhich comprises administering to a warm-blooded animal, preferably ahuman, requiring such treatment an effective amount of a crystallineform of a compound of formula I, as described above.

The size of the dose for therapeutic or prophylactic purposes of acrystalline form of a compound of formula I will naturally varyaccording to the nature and severity of the medical condition, the ageand sex of the animal or patient being treated and the route ofadministration, according to well known principles of medicine.

Suitable daily doses of the compounds of the invention in thetherapeutic treatment of humans are about 0.001-50 mg/kg body weight,preferably 0.01-10 mg/kg body weight.

A crystalline form of the compound of formula I may be administered as asole therapy or it may be administered in conjunction with otherpharmacologically active agents such as a anti-diabetic,anti-hypertensive, diuretic or anti-hyperlipidaemic agent.

Crystalline forms prepared in accordance with the Example(s) belowshowed essentially the same powder X-ray diffraction patterns and/or DSCthermograms. It was clear when comparing the relevantpatterns/thermograms (allowing for experimental error) that the samecrystalline form had been formed. DSC onset temperatures may vary in therange ±5° C. (for example ±2° C.), and powder X-ray diffraction patterndistance values may vary in the range ±5 on the last decimal place.

Abbreviations

EtOAc=ethyl acetate

HPLC=high-pressure liquid chromatography

i-PrOAc=isopropyl acetate

NMP=N-methyl-2-pyrrolidinone

THF=tetrahydrofuran

SYNTHESIS OF (S)2-ETHOXY-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl] propanoic Acid

1) Ethyl (S)-2-Ethoxy-3-(4-hydroxyphenyl)propanoate

a) Preparation of Ethyl 2-Ethoxyethanoate

A solution of 2-chloroacetic acid (50 g, 529 mmol, 1.0 eq) in absoluteethanol (110 ml, 2.2 vol. (where vol. Hereinafter means volumeequivalent) was charged to an ethanol solution of sodium ethoxide (494ml, 90 g, 1.32 mol, 2.5 vol.). The temperature during the charging waskept at 15-25° C. When the charging was completed the temperature wasraised to 50° C. The reaction mixture was cooled to 15° C. when >95%conversion was achieved. HCl (g) was then charged until the pH of themixture was <1. When the conversion was >95% the slurry was cooled to15° C. and neutralised to pH 5-7 with sodium ethoxide solution(approximately 5-20% of the initially charged amount). Afterneutralisation the slurry was cooled to 5° C. and ethyl acetate (150 ml,3 vol.) was charged. The sodium chloride formed in the reaction was thenfiltered off and washed with ethyl acetate. The solution was thenevaporated. Maximum remaining ethanol was 20 w/w %

The overall yield of the subtitle compound was 58% of the theoreticalvalue (loss was in evaporation). The chemical purity was >99%.

Preparation of Ethyl 2-Ethoxy-3-(4-methoxyphenyl)propenoate

4-Methoxybenzaldehyde (100 g, 734 mmol, 1.0 eq.) and ethyl2-exthoxyethanoate (116 g, 881 mmol, 1.2 eq.) was dissolved in THF (600ml, 6 vol.) under an atmosphere of nitrogen. The solution was cooled to−20° C. To the resulting solution, a solution of potassium tert-butoxide(98.8 g, 880 mmol, 1.2 eq) in THF (704 ml, 7.1 vol. corresponding topotassium tert-butoxide) was slowly charged while maintaining thetemperature <−10° C. After the charging was completed, the reactionmixture was stirred for 1 hour at a temperature of −50° C. to −10° C. Tothe slurry, was then charged with glacial acetic acid (53 g, 1.24 mol,1.7 eq.) maintaining the temperature at <+5° C. The THF was thenevaporated until about ⅓ remained. Toluene (824 ml, 8.24 vol.) was addedand the rest of the THF evaporated. Water (200 ml, 2 vol.) andmethanesulfonic acid (50 ml, 0.5 vol.) were added to the toluene slurryto give a pH in the water layer of 2-3. The water layer was separatedoff. The toluene layer was then evaporated to remove the remainingwater. To the toluene solution was added methanesulfonic acid (2.11 g,22 mmol, 0.03 eq). The toluene solution was refluxed with a Dean-Starkedevice connected until full conversion was achieved. The solution wascooled to 25° C. The solution was then washed with sodium hydroxide(aq., 48%) (1.83 g, 22 mmol, 0.03 eq.) diluted in water (15 ml).

The overall yield of the subtitle compound was approximately 52% of thetheoretical value.

c) Preparation of 2-Ethoxy-3-(4-methoxyphenyl) propenoic Acid

NaOH (aq., 48%) (122 g, 1.46 mol, 2.0 eq.), water (244 ml, 2.44 vol.)and EtOH (90 ml, 0.9 vol.) were charged to the toluene solution of ethyl2-ethoxy-3-(4-methoxyphenyl) propenoate (approximately 96 g, 382 mmol,0.52 eq.). The reaction mixture was heated to 50° C. and stirred untilfull conversion was achieved. After the reaction was complete, thetoluene layer was separated off and the water layer was then washed withtoluene (100 ml, 1 vol.). After separation, the water layer was cooledto +5° C. and acidified with conc. HCl (approximately 173 ml, 2.1 mol,2.9 eq.). The temperature was kept <10° C. during the charging of theacid. EtOAc (100 ml, 1 vol.) was added to the acidic water slurry. Afterextraction the phases were separated. The EtOAc solution was evaporatedand toluene (288 ml, 3 vol.) was added.

The toluene solution was seeded with 2-ethoxy-3-(4-methoxyphenyl)propenoic acid and cooled to 0° C. After crystallisation the materialwas filtered. The wet substance was used without drying in thesubsequent step.

The overall yield of the subtitle compound was 42% of the theoreticalvalue for step b) and c) together. The chemical purity was 99.7 %.

d) Preparation of 2-Ethoxy-3-(4-methoxyphenyl) propanoic Acid

Palladium on charcoal (5%, 60% water wet) (13.2 g, 0.26 g Pd, 2.44 mmolPd, 0.0054 eq.) was charged to a solution of2-ethoxy-3-(4-methoxyphenyl) propenoic acid (100 g, 450 mmol, 1.0 eq.)in ethanol (800 ml, 8 vol.) under a nitrogen atmosphere. The vessel wasthen pressurised with hydrogen to 4 bar total pressure. Thehydrogenation was continued until full conversion was achieved. Thecatalyst was filtered off and the ethanol was evaporated under vacuum.Toluene (500 ml, 5 vol.) was added and then evaporated off. The residuewas dissolved in toluene (500 ml, 5 vol.) and evaporated to a volume of260 ml. The solution was heated to 50° C. and isooctane (800 ml, 8 vol.)was added. The solution was cooled to 35° C. and then seeded with2-ethoxy-3-(4-methoxyphenyl) propanoic acid. The temperature wasmaintained at 35° C. for 30 min. The thin slurry was then cooled at arate of 10° C./hour down to +5° C. which was maintained overnight. Thecrystals were then filtered off and washed with isooctane (220 ml, 2.2vol.) The crystals were dried under vacuum at 30° C.

The yield of the subtitle compound was 88% of the theoretical value. Thechemical purity was 99.8 %.

e) Preparation of(1S)-1-(1-Naphthyl)-1-ethanaminium(2S)-2-ethoxy-3-(4-methoxyphenyl)propanoate

A solution of 2-ethoxy-3-(4-methoxyphenyl) propionic acid (100 g, 446mmnol, 1.0 eq.) in i-PrOAc (2000 ml, 20 vol.) was stirred at 0-5° C.under a nitrogen atmosphere. (S)-1-(1-naphthyl) ethylamine (45.8 g, 268mmol, 0.6 eq.) was added to the resulting solution. The resultingsuspension was heated to 75-80° C. to dissolve all particles, therebyachieving a solution. The solution was then cooled and seeded with(2S)-2-ethoxy-3-(4-methoxyphenyl) propanoic acid (S)-1-(1-naphthyl)ethylamine salt. The desired diastereomeric salt was collected byfiltration. The crystals were washed with i-PrOAc.

The (2S)-2-ethoxy-3-(4-methoxyphenyl) propanoic acid (1S)-1-(1-naphthyl)ethylamine salt obtained (67 g, 169 mmol, 1.0 eq.) was dissolved byheating to 75-80° C. in i-PrOAc (1340 ml, 20 vol.). The product obtainedwas collected by filtration, washed with i-PrOAc and dried under vacuum,at 40° C., to a constant weight.

The overall yield over the two crystallisation steps was 74% of thetheoretical value. The chemical purity was >99%. The enantiomeric excess(e.e.) was 97.8%.

f) Preparation of (S)-2-Ethoxy-3-(4-hydroxyphenyl)propanoic Acid

(2S)-2-Ethoxy-3-(4-methoxyphenyl) propanoic acid (IS)-1-(1-naphthyl)ethylamine salt (100 g, 253 mmol, 1.0 eq.) was suspended in toluene. Themixture was then treated with NaOH (11.1 g, 278 mmol, 1.1 eq.) in water(280 ml, 5 vol.). The upper toluene layer containing the chiral aminewas separated. The lower aq. layer was washed with two more portions oftoluene (280 ml, 5 vol.). The lower aq. layer was acidified to pH=1 withaq. 37% HCl (30 g, 304 mmol, 1.2 eq.). The water solution containing(S)-2-ethoxy-3-(4-methoxyphenyl) propanoic acid was extracted with twoportions of EtOAc (280 ml, 5 vol.). The combined EtOAc extract waswashed with one portion of water (280 ml, 5 vol.). The solvent wasreplaced with NMP under reduced pressure.

NaOH (beads) (45.5 g, 1.14 mol, 4.5 eq.) and octanethiol (129 g, 154 ml,884 mmol, 3.5 eq.) were charged to the solution of(S)-2-ethoxy-3-(4methoxyphenyl) propanoic acid (approximately 56.6 g,253 mmol, 1.0 eq.) in NMP (680 ml, 12 vol.) under a nitrogen atmosphere.The reaction mixture was heated to 120° C. and kept at 115-125° C. untilthe reaction was complete as determined by HPLC.

The reaction mixture was cooled to 60° C. and then quenched with water.The pH was then adjusted to 2-3 with conc. HCl. The temperature wasmaintained at 60-70° C. Two layers were formed, the upper layer of whichcontaining mainly octanethiol and the corresponding methyl ether (formedin the reaction). The layers were separated and the layer containingwater and NMP was concentrated to 34 volumes under vacuum at 80-100 ° C.inner temperature.

The residue was extracted with a mixture of H₂O:EtOAc. The EtOAcsolution was subsequently washed 3 times with a 15% NaCl solution.

The EtOAc was evaporated and the residue was directly used in thesubsequent step or could also be crystallised from toluene to yield awhite solid.

The yield was 52% using crystallisation, 90% using only evaporation. Thechemical purity was 99.8%. The enantiomeric excess (e.e.) was 97.8%.

g) Preparation of Ethyl (S)-2-Ethoxy-3-(4hydroxyphenyl)propanoate

(S)-2-Ethoxy-3-(4-hydroxyphenyl) propanoic acid (874 g, 4.16 mol, 1.0eq.) was dissolved in EtOAc (1250 ml). To this solution were chargedethanol (3000 ml) and HCl (37%, aq.) (40 ml, 0.48 mol, 0.12 eq.). Thesolution was heated to boiling (about 72° C.) and water/EtOAc/EtOH (2000ml) was distilled off. Another portion of EtOH (2000 ml) was charged andanother 2000 ml was distilled off. This procedure was repeated oncemore. At this point approximately 95% conversion was reached. Then EtOH(99.5%, 1000 ml) was added and evaporated off. This was repeated until aconversion of >97.5% was achieved. The solution was then concentrated toa volume of 1700-2000 ml under vacuum and then cooled to 20° C.

The EtOAc solution containing ethyl (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoate was then charged slowly (30-40 min) under vigorous stirringto a solution of NaHCO₃ (7% w/w, 3500 ml). Crystallisation occurredafter a few minutes. After charging, the slurry was cooled to 0-5° C.and then stirred at 0-5° C. for at least one hour. The crystals werethen filtered off and dried under vacuum.

The yield was about 93%. The chemical purity was >99%. The enantiomericexcess (e.e.) was >97.8 %.

2) 2-(4-(Methanesulfonyloxyphenyl)ethylmethanesulfonate

2-(4-Hydroxyphenyl)ethanol (356 g, 2.58 mol, 1.0 eq) was dissolved inmethylene chloride (3500 ml) and triethyl amine (653 g, 6.44 mol, 2.5eq). The mixture was cooled to −20° C. Methanesulfonyl chloride (657 g,5.74 mol, 2.2 eq) was then added keeping the temperature between −25° C.and −15° C. When the conversion was >95%, the salt formed during thereaction was filtered off and washed with methylene chloride (600 ml).The organic layer was washed first with saturated sodiumhydrogencarbonate solution (700 ml) at 20° C. followed by water (700ml). The methylene chloride was evaporated and replaced by acetonitrile.The acetonitrile solution was then used in the subsequent step.

3) Ethyl(S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxylphenyl]propanoate

Ethyl (S)-2-ethoxy-3-(4-hydroxyphenyl) propanoate(325 g, 1.34 mol, 1.0eq) was dissolved in acetonitrile (2600 ml). When a homogenous solutionwas formed, potassium carbonate (560 g, 4.05 mol, 3.0 eq) and magnesiumsulfate (110 g, (0.2 g/g K₂CO₃)) was added. The acetonitrile solution of2-(4-(methanesulfonyloxyphenyl)ethylmethanesulfonate (total volume ca:2050 ml (0.3 g/ml, 2.21 mol, 1.65 eq)) was charged to the reactionvessel and the mixture allowed to react at reflux, 82° C. for 24 hourswith vigorous stirring, keeping the volume constant by portion-wiseaddition of acetonitrile. When a conversion >98% was reached thereaction was cooled to room temperature. The remaining salts werefiltered off and washed with acetonitrile (800 ml). The filtrate wasevaporated to dryness. The residue was then used in the subsequent step.

4)(S)-2-Ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoicAcid

To the oil of ethyl(S)-2-ethoxy-3-[4(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoate(723 g (71.2% assay), 1.18 mol. 1.0 eq) was added THF (3900 ml). When ahomogenous solution was formed, water (900 ml) was added. The mixturewas cooled to +10° C. Lithium hydroxide solution (390 ml, 4 M, 1.32 eq)was added over 1 hour. The temperature was then raised to +30° C. andthe reaction allowed to proceed at this temperature for 2-3 hours. Thereaction was stopped when the conversion was >99%. EtOAc (500 ml) wasadded and the mixture cooled to room temperature. The solution wasstirred for about 30 minutes and the THF was evaporated off. When about80-90% of the THF was evaporated, water (1900 ml) was added. Theevaporation was continued until no THF remained in the mixture. Thealkaline water solution was then washed with EtOAc (1000 ml, 2×1250 ml,and 950 ml). The pH of the water solution of(S)-2-ethoxy-3-[4(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoicacid was then adjusted to 2.0-2.5 with HCl (aq) (550 ml, 3.0 M). EtOAc(2500 ml) was added and the phases separated. The ethyl acetate solutionof(S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoicacid was then washed with water (700 ml) and after separation evaporatedto dryness. The remaining oil was then used in the followingcrystallisation.

Crystallisation of(S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoicAcid

The crude material from 3 batches of(S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoicacid (1871 g total weight, 1262 g compound, 3.09 mol, 1.0 eq) containingEtOAc (500 ml) was dissolved in toluene (5000 ml) at 50° C. When a clearsolution was achieved the solution was evaporated to decrease the amountof EtOAc present. The volume before evaporation was 6750 ml. Anotherportion of toluene (2500 ml) was added, volume after addition was 7750ml, and evaporation was continued. A third portion of toluene (2500 ml)was then added to the solution, the volume before the addition was 6300ml, the volume after the addition was 8800 ml. The evaporation wascontinued until an opaque solution was formed, volume 8200 ml. Isooctane(1000 ml) was added to the solution which had been heated to 40° C. Thecrystallisation was initiated by seeding at 40° C. The mixture wasvigorously stirred until a slurry was formed. The agitation rate wasthen decreased. The slurry was left crystallising over night. The slurrywas then filtered and washed with toluene:isooctane 5:1 (1800 ml). Thecrystals were then dried under reduced pressure at 40° C.

Recrystallisation of(S)2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoicAcid

(S)-2-Ethoxy-3-[4(2-{(4methanesulfonyloxyphenyl}ethoxy)phenyl]propanoicacid (1040 g (96.4% assay), 2.45 mol, 1.0 eq) was dissolved in toluene(7000 ml) at a temperature of 60° C. When a clear solution was achievedisooctane (1720 ml) was added to the solution. The solution was thenfiltered through Silica 60 gel. The solution was then cooled from 50° C.to 45° C., at this temperature crystallisation occurred. The slurry wascooled to 20° C. The solid was then filtered and washed withtoluene:isooctane 5:1(1500 ml). The crystals were dried under reducedpressure at 40° C.

Melting Point Determination

Differential scanning calorimetry (ISC) was performed using a MettlerDSC820 instrument, according to standard methods, for example thosedescribed in: Höhne, G. W. et al (1996), Differential ScanningCalorimetry, Springer, Berlin. DSC of the anhydrous form showed anendotherm with an extrapolated onset temperature of ca 87° C. (ca 102J/g)

X-ray Powder Diffraction Pattern Determination

The X-ray powder diffractograms (XRPD) were determined using a SiemensD5000 X-ray diffractometer and/or a Philips X'Pert MPD X-raydiffractometer. XRPD was performed on samples prepared according tostandard methods, for example those described in: Giacovazzo, C. et al(1995), Fundamentals of Crystallography, Oxford University Press;Jenkins, R. and Snyder, R. L. (1996), Introduction to X-Ray PowderDiffractometry, John Wiley and Sons, New York; Bunn, C. W. (1948),Chemical Crystallography, Clarendon Press, London; or Klug, H. P. andAlexander, L. E. (1974), X-Ray Diffraction Procedures, John Wiley andSons, New York.

The crystals of an anhydrous form were analyzed by XRPD and the resultstabulated below in Table 1 (in which RI represents relative intensity).The diffractogram was measured with variable slits and without internalstandard. The intensities were based on the intensities observed in avariable slit measurement without background subtraction. The relativeintensities are less reliable, and instead of numeric values, thefollowing definitions are used:

% Relative Intensity Definition  25-100 vs (very strong) 10-25 s(strong)  3-10 m (medium) 1-3 w (weak)

Some additional weak or very weak peaks found in the diffractogram havebeen omitted from Table 1.

TABLE 1 X-ray powder diffraction data for an anhydrous form of acrystalline form of a compound of formula I. d-value/Å RI d-value/Å RId-value/Å RI 12.3 w 3.64 s 2.74 w 9.4 m 3.60 s 2.72 m 7.2 m 3.56 m 2.67w 6.9 m 3.45 s 2.60 w 6.2 vs 3.43 m 2.45 w 5.3 m 3.35 w 2.35 w 5.2 w3.29 w 2.31 w 4.90 w 3.26 m 2.20 w 4.69 s 3.17 w 2.18 w 4.47 vs 3.12 m2.11 w 4.42 m 3.10 w 2.08 w 4.22 m 3.03 w 2.02 w 4.15 vs 2.95 w 1.99 w4.08 w 2.85 w 1.93 w 3.95 w 2.80 m 3.79 w 2.78 w

It will be understood that the d-values of the X-ray powder diffractionpatterns may vary slightly from one instrument to another and so thevalues quoted are not to be construed as absolute. It is reasonable toassume that a crystalline form of a compound of formula I is that whichis described herein if the d-values are within ±5 on the last decimalplace, especially if within ±2 on the last decimal place.

Single Crystal X-Ray Diffraction Pattern Determination

A unit cell was determined from single crystal X-ray data of theanhydrous form. It was orthorhombic with P2₁2₁2₁ symmetry, Z=4, and thefollowing dimensions: α=5.762 Å, b=14.426 Å, c=24.785 Å, α=β=γ=90° andV=2060.2 Å³.

What is claimed is:
 1. A crystalline form of the compound(S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoicacid, shown in formula I below,

which is substantially or essentially free of solvent and which has amelting point of between 82 and 92° C., an X-ray powder diffractionpattern containing specific peaks of high intensity at 6.2, 4.47 and4.15 Å, and additional specific peaks of lower relative intensity to thefirst peaks at 4.69, 3.64, 3.60 and 3.45 Å.
 2. A pharmaceuticalformulation comprising a crystalline form of a compound of formula I, asdefined in claim 1, and a pharmaceutically acceptable adjuvant, diluentor carrier.
 3. A method for treatment or prophylaxis of conditionsassociated with reduced sensitivity to insulin, which method comprisesadministering a therapeutically effective amount of a compound accordingto claim 1 to a patient having such reduced sensitivity to insulin.
 4. Amethod for treatment or prophylaxis of a disorder selected from thegroup consisting of dyslipidaemia, type 2 diabetes mellitus,hyperglycaemia, hyperinsulinaemia, arterial hypertension, abdominalobesity and any combination thereof, which method comprisesadministering a therapeutically effective amount of a compound accordingto claim 1 to a patient in need of such treatment or prophylaxis.
 5. Aprocess for the preparation of a crystalline form of the compound offormula I according to claim 1 from a non-crystalline form, whichcomprises dissolution of the non-crystalline compound in an appropriatesolvent system followed by crystallization of the non-crystallinecompound from the solvent system by attaining supersaturation, bysolvent evaporation and/or by addition of an anti-solvent.